Aralkyl ester soft drugs

ABSTRACT

The present invention describes a method for programming a specific course and rate of metabolism for a parent drug compound that leads to an inactive or very weakly active and nontoxic metabolite when the modified drug compound is administered. The parent drug compound is modified by forming one or more of a predetermined chemical arrangement within the parent drug structure where the chemical arrangement is A-Ø-(R)—X—R′; where A is absent or is a tether moiety which allows for a metabolically stable chemical connection to be made to the parent drug compound; Ø is a substituted aryl or heteroaryl system that is already present within the parent drug compound or is specifically added to the parent drug compound via A; R is an alkyl or alkene containing chain either branched or unbranched from 0 to 10 carbons that is either also already present within the parent drug compound or is specifically added to the parent drug compound via connection to Ø; X is a carboxyl, sulfoxyl or phosphatyl function that is specifically added to the parent drug compound via connection to R; and, R′ is an added alkyl, alkenyl, or aralkyl group either branched or unbranched containing from 1 to 10 carbons, other common leaving group, or a structural element already present as an inherent portion of the parent drug compound.

BACKGROUND AND SIGNIFICANCE OF THE INVENTION

[0001] Pharmaceutical agents or drugs exhibit desirable therapeuticproperties because they contain distinct molecular arrangements calledpharmacophores. Oftentimes, however, the pharmacophores or the presenceof other chemical components within such compounds, provide a less thanideal overall profile relative to the final deployment of a given drugfor a particular clinical indication. In some cases this situation canbe improved by altering chemical features associated with a drug'sdistribution, metabolism or elimination (DME). This process, whensuccessful, results in what is now referred to in the pharmaceuticalcommunity as a “soft drug” version of the original or parent drugcompound: Soft Drugs. XX. Design, Synthesis and Evaluation ofUltra-ShortActing beta-Blockers, H.-S. Yang, W.-M. Wu and N. Bodor,Pharm. Res., 12, 329 (1995); and Synthesis and Enzymatic Hydrolysis ofEsters, Constituting Simple Models of Soft Drugs, M. Graffner-Nordberg,K. Sjodin, A. Tunek and A. Hallberg, Chem. Pharm. Bull., 46, 591 (1998).

[0002] However, unless there is compelling preclinical data whichsuggests that the clinical application of a lead compound is going tobecome problematic, DME-related features are typically not rigorouslyevaluated in a chemical manner during the early process of new drugdiscovery and development. This situation has arisen, in part, becausesubstantial clinical experience is often required to accurately definethe sometimes subtle parameters of an undesirable DME feature relativeto the beneficial aspects of a new drug while the latter is within theclose purview of its actual clinical use in a specificpathophysiological setting. The problem of not knowing exactly what DMEand toxicity-related properties may need to be addressed is additionallyconfounded by not having ready chemical blueprints for how to generallyproceed even when a particular DME or toxicity issue becomes suspected.

[0003] The invention disclosed herein provides a ready method foraltering DME and toxicity-related properties by deploying a specificchemical blueprint. The approach is useful to initially assess the DMEparameters for an entire family of potential new drug candidatepossibilities during the family's very early stages of structuralrefinement and preclinical study. When applied in this fashion, theinventive method expedites and improves the efficiency of the overallprocess of drug discovery and development.

[0004] Technologies which can enhance the efficiency of the drugdiscovery and development process have recently become of very highinterest to the global pharmaceutical enterprise: Lead Generation andOptimization, Annual Meeting Strategic Research Institute, San Diego,Jun. 23, 1997; Emerging Technologies for Drug Discovery, InternationalBiotechnology Event National Management Health Care Congress, Boston,May 19, 1997; and Pharmaceutical Education, Interim Meeting, AmericanAssociation Colleges Pharmacy, Washington, D.C., Mar. 2, 1997.

[0005] Of equal significance but in more succinct and individuallydirected applications, the present invention is also useful formodifying the clinically established pharmaceutical agents where thespecific therapeutic/side-effect details and benefits that might beassociated with such DME alterations to a parent drug molecule arealready recognized for a given indication. The current move toindividualize drug treatment protocols within the evolving field ofpharmacogenetics further underscores the very high interest andimportance for having conveniently deployable technologies which can begenerally applied toward fine-tuning and tailoring the overallpharmacological profile of a given drug for a given indication within agiven individual: Recommendations of the NIGMS WorkingGroup-Understanding Individual Variations in Drug Responses: FromPhenotype to Genotype, R. M. Long and R. M. Weinshilboum, NIH Report<http://www.hih.gov/nigms/news/reports/pharmacogenetics.html>, 5 pages(Jun. 9-10, 1998).

SUMMARY OF THE INVENTION

[0006] The present invention relates to a method of deploying one ormore aralkyl ester moieties or “metabophores” within a parent drugcompound. The aralkyl ester moieties are either co-constructed withinthe constitutive molecular framework of a parent drug compound or areadded onto a parent drug compound as a distinct appendage. In allinstances these constructions are done in such a manner so as topreserve the parent drug's therapeutical properties while programming aspecific course for the drug's metabolism. The specific course for thedrug's metabolism leads to inactive or much less active, non-toxicmetabolites when the modified drug is then administered to humans byeither the oral, inhalation, injection, implantable or topical routes.

[0007] Furthermore, the specific molecular details of the aralkyl estermoieties and their various placements within the parent drug's structureare able to be fine-tuned to precisely control the rate of metabolism.The rate of metabolism, in turn, can be used to control thedistribution, the duration of action, the elimination, and/or thetoxicity of the resulting soft drug.

[0008] The present invention is useful for all drug types whenever theprogrammed ester cleavage causes fragmentation of the drug's inherentpharmacophore or leads to the production of an acidic group that can notsomewhere by tolerated by the pharmacophore within the still intactparent drug.

[0009] The present invention is useful for producing families of closelyrelated compounds for better optimizing the overall pharmacologicalprofiles of new drug candidates during the process of drug design anddevelopment.

[0010] The present invention is also useful for enhancement of theoverall therapeutic profiles for a wide variety of drugs already beingused.

[0011] In one aspect of the present invention, the metabophores are usedto program a specific course of innocuous metabolism/elimination inorder to circumvent unwanted accumulation and/or toxic pathwaysotherwise exhibited by the parent drug.

[0012] In another aspect, the present invention is used to program therate for a specified metabolism in order to adjust the parent drug'sduration of action to a desired shorter time interval. Alternatively,when the aralkyl ester moieties of the present invention are used inconjunction with an implant or drug depot delivery system, the rate ofprogrammed metabolism can be matched to that for the soft drug'sdelivery so as to precisely provide prolonged steady-state levels of thesoft drug at pre-calibrated concentrations.

[0013] In another aspect, the present invention is used to program anultra-short duration into a parent drug to allow the resulting softdrug's actions to be under precise moment-to-moment control via itsintravenous administration infusion rate, an overall drug property whichhas already been demonstrated to be particularly useful in critical careand surgical settings. Given the paucity of drugs and drug-relatedtechnologies that have been previously targeted for very young humans,the present invention is especially useful in the development of aralkylester soft drugs which are conveniently and safely deployed for thespecific treatment of premature, full-term newborn or for the perinataland neonatal populations in general.

[0014] In yet another aspect of the present invention, the metabophoreis useful to provide an ultra-short duration drug which allows forlocalizing the effects of the soft drug when the drug's initial deliveryor activation within a desired compartment can also be achieved in aselective manner (e.g. localized injection, implant, surgical sutures,or localized photodynamic activation).

[0015] In still yet another aspect of the present invention, themetabophores are useful to provide a soft drug pharmacological agentthat can be deployed by the intravenous route to wean a patient off of aparent drug whose pharmacological action is more safely removed in acontrolled, step-wise manner by progressively decreasing the rate of theintravenous drip of the soft drug version (e.g. avoidance of re-boundpharmacological events due to abrupt withdrawal of the parent compound).

[0016] Finally, the present invention is useful with drugs which areadministered topically to the skin, eye or nasal passageways in order toeliminate or lessen any unwanted effects that the parent drugs mightotherwise exhibit upon their absorption into the systemic circulation.

DESCRIPTION OF THE DRAWINGS

[0017]FIG. 1 shows Structure 1 which is propranolol, a prototypicalaryloxypropanolamine beta-adrenergic receptor blocking agent which isused clinically and has a long duration of action (i.e. several hourhalf-life). Structure 2 is esmolol, which is also a beta-blocker usedclinically (Brevibloc®) but was designed to have an ultra-short durationof action (i.e. ten minute half-life) as a result of an appended“external” ester (note carboxyl moiety extended from the southern regionof the overall molecule). Structure 3 is another ultra-short actingbeta-blocker which has an ester within or “internal” to the parentaryloxypropanolamine pharmacophore (note centralized location of thecarboxyl moiety within the overall molecule).

[0018]FIG. 2 shows Structure 4 which is2,6-bis(1-pyrrolidinylmethyl)-4-benzamidophenol, an antiarrhythmic drugcandidate. Structure 5 represents a series of external ester-containingderivatives of 4 that provides a complimentary family of potential softdrug versions of the parent having variously shortened durations ofaction.

[0019]FIG. 3 shows a schematic representation of the chemical elementsshowing a “metabophoric” blueprint for placement within clinically useddrug molecules and/or for elaboration within new drug candidatecompounds undergoing development for use within the clinic. In Structure6: A is an attachment or tether functionality when B is not an inherentportion of the parent drug molecule; B is an aryl or heteroaryl system;C is alkyl or an alkene chain; D is carboxyl (—CO₂—), sulfoxyl (—SO₃—)or a phosphatyl function (—PO₃<); and E is alkyl, aralkyl or anadditionally derivatized leaving group. In certain embodiments, A may bedeleted because B or both B and C are already present as an inherentportion of the parent structure. For example, when A is absent, B issubstituted phenyl, C is ethyl, D is carboxyl and E is methyl, thenStructure 6 defines the southern portion of Structure 2 plus itsrelationship to the phenyl ring in the right-half portion of thenaphthalene system within Structure 1 wherein the latter is an inherentportion of the prototypical β-blocker pharmacophore. In Structure 7: Emay also be (or become attached to) a required pharmacophoric componentof the parent drug compound. In this embodiment, the ester metabophore Dis thus encompassed from both sides within the parent structure'spharmacophore (e.g. as in Structure 3 within FIG. 1) as opposed to isresidence as an appendage (e.g. as in Structure 2 within FIG. 1). Thus,when A is absent, B is ortho-flurophenyl, C is absent (alkyl case—(CH₂)_(n)— where n=0), D is carboxyl and E is a methylene attached to aportion of the parent pharmacophore, then Structure 7 defines the keymetabophoric placement within Structure 3 of FIG. 1.

[0020]FIG. 4 shows the structural similarities between the esmololStructure 2, a new target molecule Structure 8, and Structure 9 which isclonidine, a prototypical α₂-adrenergic receptor agonist whosebeneficial clinical effects are mediated centrally. A complementaryoverlap involving the key elements of the partially appended (external)metabophore within Structure 2 and a significant portion of therequisite pharmacophore within Structure 9 can be found to co-residewithin the. phenyl-ring of Structure 8.

[0021]FIG. 5 shows a representation of the backbone chain folding ofE-coli dihydrofolate reductase containing a bound methotrexate moleculeas derived from a computer-generated plot of all atoms in the drug andall a-carbon atoms of the enzyme. Strands of the central pleated sheetare shown as wide arrows.

[0022]FIG. 6 shows structures of methotrexate (Structure 10) and of ametabolically labile internal ester target form (Structure 11), in whicha simple ester bond is deployed as a metabophoric replacement for theparent structure's amide bond.

[0023]FIGS. 7-25 show further examples of the inventive method'smetabophore placed within a parent molecular framework for a wide arrayof established pharmaceutical agents that are used clinically.

DESCRIPTION OF THE INVENTION

[0024] The present invention relates to a method for programming aspecific course and rate for a parent drug compound's metabolism thatleads to an inactive or very weakly active and non-toxic metabolite whenthe parent drug compound is administered to humans by either the oral,injection, inhalation, implatable or topical routes. The methodcomprises modifying the parent drug compound by forming one or more of amodifying the parent drug compound by forming one or more of apredetermined chemical arrangement within the parent drug compound. Thechemical arrangement comprises A-Ø-(R)—X—R′ where A is absent or is atether moiety which allows for a metabolically stable chemicalconnection to be made to the parent drug compound. Ø is a substitutedaryl or heteroaryl system that is already present within the parent drugcompound or is specifically added to the parent drug compound via A. Ris an alkyl or alkene containing chain either branched or unbranchedfrom 0 to 10 carbons that is either already present within the parentdrug compound or is specifically added to the parent drug compound viaconnection to Ø. X is a carboxyl, sulfoxyl or phosphatyl function thatis specifically added to the parent drug compound via connection to R.R′ is an added alkyl, alkenyl, or aralkyl group either branched orunbranched containing from 1 to 10 carbons; other common leaving group;or, a structural element already present as an inherent portion of theparent drug compound. The chemical arrangement is not used in connectionwith specific structural settings where the parent drug compound is anaryloxypropanolamine, a 2,6-bis(1-pyrrolidinylmethyl)-4-benzamidophenol,or where the parent drug already contains an ester moiety as an inherentcomponent of its structure that also causes the parent drug to alreadyexhibit a short duration of action as would be the specific cases forthe classical short-acting drugs succinylcholine and procaine.

[0025] In a preferred method only one chemical arrangement is used. Incertain preferred embodiments, X is carboxyl. In other embodiments, Rand R′ are unbranched alkyl from 1 to 2 carbons. In still otherembodiments, R′ is a structural element already present as an inherentportion of the parent drug.

[0026] The modified drug is used to optimize the overall pharmacologicalprofile of a new drug candidate during the process of drug design anddevelopment. Alternatively, the modified drug is used to enhance theoverall therapeutic profile of a parent drug already being used in theclinic. The programmed metabolism of the added chemical arrangementserves to circumvent unwanted accumulation of the drug and to circumventone or more toxic metabolic pathways.

[0027] The programmed rate of metabolism for the added chemicalarrangement is adjusted to produce a shorter duration of action for themodified drug as compared to the parent drug. The shorter durationallows the actions of the modified drug to be under precisemoment-to-moment control by adjustment of the infusion rate of themodified drug when administered intravenously. The intravenousadministration is used to treat critical care patients and to treatneonates.

[0028] The intravenous administration is also used to wean a patient offan unmodified parent drug whose similar pharmacological action is moresafely removed in a controlled, step-wise manner by progressivelydecreasing the rate of the intravenous drip of the modified drug. Theshorter duration allows the actions of the modified drug to remainlocalized when the initial delivery or activation of the modified drugis targeted to a specified compartment by use of localized injection orimplant materials, or by localized photodynamic activation of themodified drug. In certain embodiments, the implant is a type ofsurgical-related material or suture where the modified drug is anantibiotic or a compound that promotes healing.

[0029] According to the present invention, the programmed rate ofmetabolism of the modified drug is matched with a, release rate from asustained-release injectable formulation or implant of the modified drugto provide for prolonged steady-state levels of the modified drug atpre-calibrated concentrations.

[0030] Also, according to the present invention, the modified drug isused as a topical treatment in order to eliminate or lessen unwantedeffects that the unmodified parent drug exhibits upon systemicabsorption after placement on the skin or within the eye or nasalpassageways.

[0031] The method of the present invention is especially useful wherethe parent drug plus added chemical arrangement comprises a short-actinganti-cholinergic agent. In certain embodiments, the short-actinganti-cholinergic agent is an atropine derivative that is designed fortopical administration to the eye. In other embodiments, theshort-acting anti-cholinergic agent is a non-depolarizing neuromuscularjunction blocking agent that is designed for use by the intravenousroute during surgical-related procedures.

[0032] Also, the method the present invention is especially useful wherethe parent drug plus added chemical arrangement comprises an ultra-shortacting alpha₁-adrenergic receptor blocker or an alpha₂-adrenergicreceptor agonist.

[0033] The method of the present invention is also useful where theparent drug plus added chemical arrangement comprises a short-actinginhibitor of the sodium channel. In certain embodiments, theshort-acting inhibitors are administered as sustained-release orimplantable dosage forms.

[0034] Still other uses of the method of the present invention includeuses in which the parent drug plus the added chemical arrangementcomprises an ultra-short acting ACE inhibitor; an ultra-short actinghistamine receptor blocker; an ultra-short acting adenosine antagonist;an ultra-short acting anti-inflammatory agent; an ultra-short actingantiarrhythmic agent; and, an ultra-short acting calcium channelblocker.

[0035] Still further uses of the method of the present invention includeuses in which the parent drug plus the added chemical arrangementcomprises an ultra-short acting antibiotic compound includingsulfonamide, penicillin, cephalosporin or tetracycline. In certainembodiments, the ultra-short acting antibiotic compounds areadministered via their impregnation in surgical suture material orwound-healing implantable polymeric materials.

[0036] Yet another use of the method of the present invention includes ause in which the parent drug plus the added chemical arrangementcomprises a short-acting version of methotrexate. In certainembodiments, the short-acting version of methotrexate is administeredtopically. The present invention is especially useful where the topicaladministration is used to treat epidermoid cancers or psoriasis.

[0037] Referring now to Structures 2 and 3 in FIG. 1, the indicatedmetabophoric functionalities were previously incorporated intopropanol-like structures to produce ultra-short acting beta-adrenergicreceptor blocking agent soft drugs: Method for Treatment or Prophylaxisof tetra-substituted Cardiac Disorders (Aryl Esters), P. W. Erhardt, R.J. Borgman and J. P. O'Donnell, U.S. Pat. No. 4,387,103 (1983); Methodfor Treatment or Prophylaxis of Cardiac Disorders (Aryl Esters), P. W.Erhardt, R. J. Borgman and J. P. O'Donnell, U.S. Pat. No. 4,593,119(1986); Method for Treatment or Prophylaxis of Cardiac Disorders(Internal Esters), S. T, Kam, P. W. Erhardt, R. J. Borgman and J. P.O'Donnell, U.S. Pat. No. 4,405,642 (1983); Compounds and Method forTreatment or Prophylaxis of Cardiac Disorders (N-External Esters), P. W.Erhardt and R. J. Borgman, U.S. Pat. No. 4,450,173 (1984); Compounds forTreatment or Prophylaxis of Cardiac Disorders (Internal Esters), R. J.Borgman, P. W. Erhardt, S. T. Kam and J. P. O'Donnell, U.S. Pat. No.4,604,481 (1986); Esters of Thiadiazole Oxypropanolamine Derivatives andPharmaceutical Uses, P. W. Erhardt and W. L. Matier, U.S. Pat. No.4,623,652 (1986); Esters of3-(3-substituted-Amino-2-Hyroxypropoxy)-4-Substituted-1,2,5-ThiadiazoleDerivatives, W. L. Matier, P. W. Erhardt and G. Patil, U.S. Pat. No.4,508,725 (1985); Ethylenediamine Derivatives of AryloxypropanolamineAryl Esters Having Various Medicinal Properties, P. W. Erhardt and C. M.Woo, U.S. Pat. No. 4,556,668 (1985); Esters or AryloxypropanolamineDerivatives and Medicinal Uses, P. W. Erhardt and W. L. Matier, U.S.Pat. No. 4,692,446 (1987); Esters of Aryloxypropanolamine Derivatives,P. W. Erhardt and W. L. Matier, U.S. Pat. No. 4,804,677 (1989); Estersof Aryloxypropanolamine Derivatives, P. W. Erhardt and W. L. Matier,U.S. Pat. No. 4,906,661 (1990); Ultra-Short Acting β-Blockers: AProposal For The Treatment Of The Critically Ill Patient, J.Zaroslinski, R. J. Borgman, J. P. O'Donnell, W. G. Anderson, P. W.Erhardt, S. T. Kam, R. D. Reynolds, R. J. Lee and R. J. Gorczynski, LifeSciences, 31, 899 (1982); Benzylamine and Dibenzylamine Revisited.Syntheses of N-Substituted Aryloxypropanolamines Exemplifying a GeneralRoute to Secondary Aliphatic Amines, P. W. Erhardt, Synth. Comm., 13,103 (1983); Ultra Short-Acting β-Adrenergic Receptor Blocking Agents. 1.(Aryloxy)propanolamines Containing Esters in the Nitrogen Substituent,P. W. Erhardt, C. M. Woo, R. J. Gorczynski and W. G. Anderson, J. Med.Chem., 25, 1402 (1982); Ultra-Short-Acting β-Adrenergic ReceptorBlocking Agents. 2. (Aryloxy)propanolamines Containing Esters on theAryl Function, P. W. Erhardt, C. M. Woo, W. G. Anderson and R. J.Gorczynski, J. Med. Chem., 25, 1408 (1982); and Ultra-Short-Actingβ-Adrenergic Receptor Blocking Agents. 3. Ethylenediamine Derivatives of(Aryloxy)propanolamines Having Esters on the Aryl Function, P. W.Erhardt, C. M. Woo, W. L. Matier, R. J. Gorczynski and W. G: Anderson,J. Med. Chem., 26, 1109 (1983). The successful development and marketingof Structure 2 (esmolol or Brevibloc®) provides an exemplary clinicalproof of utility for the present invention within the context of usingbeta-blockers in the critical care arena: Esmolol. P. W. Erhardt, inChronicles of Drug Discovery, D. Lednicer, Ed. ACS Books, Washington,D.C., U.S.A. 1993; A Prodrug and a Soft Drug. P. W. Erhardt, in DrugMetabolism: Databases and High-Throughput Testing During Drug Design andDevelopment, P. W. Erhardt, Ed. IUPAC Books, Blackwell Science, Oxford,U.K. 1999.

[0038] Referring to FIG. 2, the indicated metabophoric functionalitieshave also been previously incorporated into a novel compound, Structure4 as the latter was undergoing preclinical and early clinicaldevelopment for its potential use as a long-acting antiarrhythmic agent.A short-acting, potential soft drug version, Structure 5, was obtainedin a complimentary manner within a very limited family ofclosely-related compounds: Ester Derivatives of2,6-Bis(7-pyrrolidinylmethyl)-4-benzamidophenolas Short-ActingAntiarrhythmic Agents. 1. D. M. Stout, L. A. Black, C. Barcelon-Yang, W.L. Matier, B. S. Brown, C. Y. Quon and H. F. Stampfli, J. Med. Chem.,32, 1910 (1989); and Mono- and Bis(aminomethyl)phenylacetic Acid Estersas Short-Acting Antiarrhythmic Agents. 2. R. J. Chorvat, L. A. Black, V.V. Ranade, C. Barcelon-Yang, D. M. Stout, B. S. Brown, H. F. Stampfliand C. Y. Quon, J. Med. Chem., 36, 2494 (1993). Although these researchcompounds were not pursued into the marketplace, the ready obtainment ofa family of short-acting agents within the specific context of parentcompound Structure 4 provides a demonstration of the utility and ease ofdeploying the metabophoric technology, as specifically described herein,in a parallel manner during the preclinical and early clinicaldevelopment stages of new drug development.

[0039] Referring to FIG. 3, the structural arrangements specified byStructures 6 and 7 have similar applicability when placed within otherdrug molecules. Since the structural systems or chemical arrangementsportrayed by Structures 6 and 7 program distinct metabolic lability intoa parent molecule, they are also referred to herein as “metabophores,”by analogy to the term “pharmacophore”. The latter term is used tospecify the structural components within a drug that are requisite forthe drug's efficacious pharmacological activity. By analogy, the term“metabophore” has recently been placed within the literature todesignate the specific molecular features that are pertinent for a givenmetabolic process, such as that for the enzymatic hydrolysis reaction ofan ester moiety: Drug Metabolism Data: Past And Present Status, P. W.Erhardt, Med. Chem. Res., 8, 400 (1998); Drug Metabolism Data: Past,Present and Future Considerations, P. W. Erhardt, Metabolism Databasesand High Through-put Testing During Drug Design and Development, P.Erhardt, Ed. IUPAC Books, Blackwell Science, Oxford, U.K., 1999;Statistics-Based Probabilities of Metabolic Possibilities, P. W.Erhardt, Metabolism Databases and High Through-put Testing During DrugDesign and Development, P. Erhardt, Ed. IUPAC Books, Blackwell Science,Oxford, U.K., 1999; and Use of Metabolism Databases During The Design ofProdrugs and Codrugs, P. W. Erhardt, Metabolism Databases and HighThrough-put Testing During Drug Design and Development, P. Erhardt, Ed.IUPAC Books, Blackwell Science, Oxford, U.K., 1999.

[0040] Thus, the method of the present invention provides for thegeneral use of a distinct metabophoric chemical arrangement that isincorporated one or more times within a parent drug compound.Specifically, variations within a defined family of an arallkyl estermoiety constitute the distinct metabophoric arrangements that areincorporated one or more times into a parent drug compound such thatinitially there is a minimal impact upon the original desiredpharmacological activity exhibited by the parent drug. The metabophoreunits are subject, however, to Phase I metabolic hydrolysis by one ormore of the esterases, sulfatases, phosphatases, CYPs and the like. InFIG. 3, both the ABCD fragment and the E fragment that result from themetabolic hydrolysis are inactive or significantly less active, arenon-toxic and are subject to subsequent metabolic and/or eliminationpathways at a rate that is appropriate for a given clinical indication.Further, manipulation of the steric and electronically driven chemicalconstants associated with specific molecular aspects of the metabophoreallows for precise calibration and fine-tuning of the rate of themetabolic hydrolysis reactions.

[0041] While the exact numbers and preferred chemical embodiments forthe metabophores are ultimately dictated via optimization within eachindividual case of drug and indication, there are some arrangementswhich generally provide for the most chemically efficient andpharmacologically compatible deployments of the inventive method. In thecase of the external esters, Structure 6, the preferred embodiment oftenreflects incorporation of not more than two metabophores. In addition,for the preferred embodiment A is absent, B and C are at least partiallyderivable from structural elements already present within the parentpharmacophore, D is a carboxylic ester and E is an alkyl group. In themost preferred general embodiment only a single metabophore is utilized,C is further specified to be one or two unsubstituted carbons distantfrom B, and E is further specified to be a simple methyl or ethyl group.In the case of the internal esters, Structure 7, the generally preferredembodiment involves deployment of just one metabophore, where A isabsent, B and C are at least partially derivable from features alreadypresent within the parent pharmacophore or C is completely absent (alkyl—(CH₂)_(n)— case where n=0), D is a carboxylic ester, and E is anintegral part of the inherent pharmacophore as long as its connection toD is represented by at least one, non-sterically hindered methyleneunit. An arrangement which simultaneously deploys one internal estermetabophore plus one or two external ester metabophores is also aparticularly useful embodiment when extremely ultra-short durations ofaction are being sought for a particular indication.

[0042] Referring now to FIGS. 4 and 6, target Structures 8 and 11 depictpreferred embodiments for the respective external and internalmetabophores of the inventive method as applied to two completelydifferent types of parent molecules. To expedite drug design anddevelopment, these target structures are given the highest priority forchemical synthesis and pharmacological evaluation. Subsequent familymembers are constructed according to the specifications of Structures 6and 7 on as needed basis in order to further progress and fine-tune thenature of the metabophoric insertions and to thereby best accommodate agiven clinical indication. From these figures it can be noted that thepresent invention provides a ready blueprint for how to expeditiouslyaddress DME properties as new lead compounds proceed through the processof drug discovery and development by deploying a hierarchy of actual,practically selected, chemical structures accompanied by experimentallyderived pharmacological test results. In this context the inventivemethod, as disclosed herein, clearly distinguishes itself from thepresent trend to use theoretical or computational methods accompanied byvarious searching paradigms across real or virtual compound libraries inorder to select compounds that are then synthesized and subjected toexperimental pharmacological verification, all being done in areiterative fashion so as to finally proceed toward an applicablemetabophoric lead arrangement that might then be likewise deployed viaactual structures in a given, ongoing case of new drug development: e.g.Quantitative Structure-Metabolism Relationships: Steric and NonstericEffects in the Enzymatic Hydrolysis of Noncongener Carboxylic Esters, P.Buchwald and N. Bodor, J. Med. Chem., 42, 5160 (1999).

[0043] The inventive technology is further illustrated in FIGS. 7-25which show specific target structures and in the following exampleswhich are meant to demonstrate the wide, general applicability of theinvention while also providing a purview of how the metabophores can bespecifically incorporated across a wide variety of structural typeswithin the framework of actual chemical compounds. These representativeexamples are not intended to necessarily depict the most preferredembodiments of the invention, nor are the examples meant to be limitingin the sense of the general scope of the overall method.

EXAMPLE 1

[0044] Structure 12 represents an analog of atrorine that has anappended external ester metabophore. It has been designed for deliveryas drops to the eye where it will then display its characteristicantimuscarinic properties that are useful during eye examinations foronly about 30 minutes. Atropine's several hour duration is in largeexcess of the time typically needed to conduct a routine eye exam andchemical antidotes often need to be administered so that a patient'svision can be more quickly normalized. In addition, due to the samemetabolic programming, the soft drug analog has a better systemicside-effect profile than atropine because the soft drug that is absorbedfrom this localized topical compartment is readily deactivated.

EXAMPLE 2

[0045] Structures 13 and 14 represent metabophore-containing, bulkyanalogs of decamethonium and pancuronium, respectively. Two externalesters have been deployed in each case in order to further enhance theoverall molecules' metabolic biotransformations given that these esters'close placements to the bulky aromatic rings slow their individualmetabolic hydrolyses rates. The parent compounds' inherentanti-nicotinic activities, produced in a non-depolarizing fashion atneuromuscular junctions by virtue of the presence of the bulkyfunctionalities, has a short half-life due to the appended metabophores.These compounds are ideally suited for use during surgery where there isa long-standing need for titrable, short-acting, non-depolarizingneuromuscular junction blocking agents: Approaches to Short-ActingNeuromuscular Blocking Agents: NonsymmetricalBistetrahydroisoquinolinium Mono- and Diesters, N. C. Dhar, R. B. Maehr,L. A. Masterson, J. M. Midgley, J. B. Stenlake and W. B. Wastila, J.Med. Chem., 39, 556 (1996).

EXAMPLE 3

[0046] Structures 15 and 16 represent metabophore-containing analogs ofprazosin and indoramin, respectively. Structure 15 contains a singlesulfonate ester appendage while Structure 16 contains both an internalcarboxylate metabophore and an external phosphonate ester appendage. Inboth cases, the inherent α₁-receptor antagonist properties are displayedas an ultra-short duration such that both compounds are better used incritical care settings via the intravenous route to treat hypertensivecrises, shock or Raynaud's disease,

EXAMPLE 4

[0047] Emergency room medical practice requires a titrable, quicklyequilibrating and short action version of clonidine, Structure 9 in FIG.4. This drug is also an a-adrenergic receptor ligand. Consideration ofthe structure-activity relationships for this family of centrally actinga₂-adrenergic agonists indicates that while the two ortho-chlorosubstituents are important for establishing a twisted conformationrequired at central a₂receptors, the para-position is amenable tostructural modifications. Principles of Medicinal Chemistry, W. O. Foye,T. L. Lemke, D. A. Williams; Eds., Williams & Wilkins Publ., Baltimore,Md., p. 356 (1995). Incorporation of a single external ester metabophoreaccording to the structural blueprint provided in FIG. 3 affordsStructure 8 in FIG. 4. Since Structure 8 is a more lipophilic version ofthe parent structure, it equilibrates more quickly into the CNS whenadministered by the IV route. Thereafter, the modified soft drug versionpossesses a very short pharmacological half-life due to the metabolicliability of the added ester link coupled with the foreign look that itsresulting metabolite displays to the a-adrenergic receptor, e.g. afull-blown carboxylate anion in a region otherwise present as alipophilic aryl moiety. In addition, the titratable, short-acting analogis useful toward affecting the controlled withdrawal of these types ofparent compounds which, in turn, are useful toward preventing ‘rebound’hypertension. The structural similarities between the clonidineStructure 9, target molecule Structure 8 and the prototypical esmololStructure 2 are all shown in FIG. 4 in a side-by-side fashion.

EXAMPLE 5

[0048] Structures 17 and 18 represent metabophore-containing analogs ofphenytoin and carbamazepine, respectively. Both compounds contain twoexternal ester metabophores which serve to prompt a rapidhydrolytic-based metabolic clearance of the compounds. Because of theprogrammed and controlled elimination, both analogs are able to negatethe present high degree of variance found in the metabolism of theparent drugs, e.g. phenytoin saturates its metabolizing systems and thusits metabolism tends to slow down with time while carbamazepine inducesits metabolizing enzymes and its metabolism tends to speed up withcontinued usage. Both of the parent compounds inhibit the sodium channeland find use in the treatment of seizures. As re-designed according tothe inventive method's blueprint, these desirable properties arepreserved within the soft drug analogs. Further chemical adjustment ofthe esters' immediate steric environments within each of the analogs areable to program a specific duration of action and elimination which isthen also paired with the rate of drug released from sustained-releaseor implantable dosage forms so that very even levels of the modifieddrug's concentrations are achieved for prolonged periods of time.

EXAMPLE 6

[0049] Structure 19 represents a metabophore-containing analog ofenalaprilat. It's external aralkyl ester appendage provides a readyhandle for hydrolytic metabolism and thus renders the molecule ashort-acting version of the common ACE-inhibitor, providing that theresulting acidic moiety is not well tolerated when generated in thisparticular location. Ultimately, an effective soft drug version isconveniently deployed by the intravenous route and, having drip-ratecontrol of its actions, used more advantageously within critical caresettings.

EXAMPLE 7

[0050] Structures 20 and 21 represent metabophore-containing analogs ofdiphenhydramine and famotidine, respectively. In Structure 20 aninternal ester has been deployed while in Structure 21 an external esterhas been deployed. Because of the metabophoric placements, these analogsare short acting versions of their respective H₁-receptor blocker andH₂-receptor blocker parent compounds. The aralkyl ester soft drugs arebeneficial toward use in critical care settings as quickly titrable andcontrollable, ultra-short-acting agents when given by intravenousinfusion.

EXAMPLE 8

[0051] Structure 22 represents a titrable, quickly equilibrating andultra-short acting version of theophylline for use in critical caresettings whenever an adenosine antagonist is useful, e.g. improvingairway resistance in critical neonatal and pediatric populations.

EXAMPLE 9

[0052] Structure 23 represents a titrable, quickly equilibrating andultra-short acting version of indomethacin for use in critical caresettings whenever an intra-venous anti-inflammatory agent is useful.

EXAMPLE 10

[0053] Structure 24 represents a titrable, quickly equilibrating andultra-short acting version of lidocaine, a Class IB antiarhythmic agent.The aralkyl soft drug allows for more consistent dose-responserelationships compared to the parent drug when used by the intravenousroute in critical care settings.

EXAMPLE 11

[0054] Structures 25 and 26 represent titrable, quickly equilibratingand ultra-short acting versions of the calcium channel blockersnifedipine and verapamil, respectively. Structure 25 contains a single,external ester metabophore while Structure 26 contains an internalester, as well as a pair of external ester, metabophores. Both analogsare ideally suited for use in the critical care arena, includingneonatal populations.

EXAMPLE 12

[0055] Structures 27, 28, 29 and 30 represent metabophore-containinganalogs of sulfamethoxazole, ampicillin, cephalexin and tetracycline,respectively. All of these antibiotics are designed to exhibitultra-short durations of action which are useful not only in criticalcare settings via intravenous infusion, but are useful towardlocalization of their effects within the vicinity of polymeric materialsused as sutures or other wound-healing implantables wherein the latterhave been impregnated with any one or more of these types of antibioticsoft drugs. Toward easier elaboration of all of the methods ofadministration, all of the analogs are also designed so as to exhibitgood aqueous solubility and stability when formulated as their acidifiedsalts, e.g. as the hydrochloride salts of their amines.

EXAMPLE 13

[0056] The use of methotrexate (Structure 10 in FIG. 6) for treatingboth epidermoid cancers and severe psoriasis is an ideal situation inwhich to deploy the metabophore method of the present invention so as toeliminate systemic toxicity upon percutaneous absorption after topicaltreatments: The Physicians Desk Reference (PDR) 50^(th) ed., Publ: Med.Econ. Co., Montvale, N.J., p. 1276 (1996). Well-establishedstructure-activity relationships reveal that there are three structuralcomponents which are required for the interaction of methotrexate withits biological receptor, the latter being the enzyme dihydrofolatereductase (DHFR). Therefore, placement of a labile ester metabophorebetween any two of these elements (e.g. internal ester) results ininactive metabolites upon hydrolysis of the metabophore. This situationis shown in FIG. 5 where the Structure 10 is depicted in its interactionwith DHFR: D. A. Matthews, et al., Science, 297, 452 (1977). Theimportance of the two glutamate carboxyl groups relative to the rest ofthe molecule is clear, as is the rather non-demanding region immediatelysurrounding the glutamate-p-aminobenzoic acid amide bond. Thus,replacement of this amide bond with that of an ester is tolerable foractivity, yet allows for placement of a preferred internal-ester typemetabophore unit that when hydrolyzed, inactivates the parent molecule.A side-by-side structural comparison between methotrexate, Structure 10,and its internal ester metabophore version, soft drug Structure 11, isprovided in FIG. 6.

EXAMPLE 14

[0057]FIGS. 7-25 show further examples of the inventive method'smetabophore placed within a parent molecular framework for a wide arrayof established pharmaceutical agents that are used clinically.

[0058] One skilled in the art will readily appreciate that the presentinvention is well adapted to carry out the objects and obtain the endsand advantages mentioned, as well as those inherent therein. The presentexample along with the methods, procedures, treatment, molecules andspecific compounds described herein are presently representative ofpreferred embodiments, are exemplary, and are not intended aslimitations on the scope of the invention. Changes therein and otheruses will occur to those skilled in the art which are encompassed withinthe spirit of the invention as defined by the scope of the claims. Anypatents or publications mentioned in this specification are indicativeof the levels of those skilled in the art to which the inventionpertains. These patents and publications are herein incorporated byreference to the same extent as if each individual publication wasspecifically and individually indicated to be incorporated by reference.

[0059] Having described presently preferred embodiments of theinvention, it is to be understood that there may be other embodimentswhich are within the scope of the appended claims.

1. A method for programming a specific course and rate for a parent drugcompound's metabolism that leads to an inactive or weakly active andnon-toxic metabolite when the parent drug compound is administered,comprising modifying the parent drug compound by forming one or more ofa predetermined chemical arrangement within the parent drug compound,the chemical arrangement comprising A-φ-(R)—X—R′wherein A is absent oris a tether moiety which allows for a metabolically stable chemicalconnection to be made to the parent drug compound; φis a substitutedaryl or heteroaryl system that is already present within the parent drugcompound or is specifically added to the parent drug compound via A; Ris an alkyl or alkene containing chain either branched or unbranchedfrom 0 to 10 carbons that is either already present within the parentdrug compound or is specifically added to the parent drug compound viaconnection to φ; X is a carboxyl, sulfoxyl or phosphatyl function thatis specifically added to the parent drug compound via connection to R;and, R′ is an added alkyl, alkenyl, or aralkyl group either branched orunbranched containing from 1 to 10 carbons; other common leaving group;or, a structural element already present as an inherent portion of theparent drug compound; said chemical arrangement not being used inconnection with specific structural settings wherein the parent drugcompound is an aryloxypropanolamine, a2,6-bis(1-pyrrolidinylmethyl)-4-benzamidophenol, of wherein the parentdrug already contains an ester moiety as an inherent component of thestructure of the parent drug that also causes the parent drug to alreadyexhibit a short duration of action, or wherein the modified drugcompound consisting of a parent drug compound has a formula

and has one predetermined chemical arrangement attached to the parentdrug by a carbon-to-carbon bond at the 4-position, the predeterminedchemical arrangement having a formula R—CO₂—; wherein R consists of anunsubstituted alkyl or alkene containing chain either branched orunbranched from 0 to 10 carbons; and R′ consists of an unsubstitutedalkyl, alkenyl, or aralkyl group either branched or unbranchedcontaining from 1 to
 10. 2. The method of claim 1, in which only onechemical arrangement is used.
 3. The method of claim 2, in which X iscarboxyl.
 4. The method of claim 3, in which R and R′ are unbranchedalkyl from 1 to 2 carbons.
 5. The method of claim 3, in which R′ is astructural element already present as an inherent portion of the parentdrug compound.
 6. The method of claim 1, in which the modified drug isused to optimize the overall pharmacological profiles of a new drugcandidate during the process of drug design and development.
 7. Themethod of claim 1, in which the modified drug is used to enhance theoverall therapeutic profile of a parent drug that is used clinically. 8.The method of claim 1, in which the programmed metabolism of the addedchemical arrangement circumvents unwanted accumulation of the drug. 9.The method of claim 1, in which the programmed metabolism of the addedchemical arrangement circumvents one or more toxic metabolic pathways.10. The method of claim 1, in which a programmed rate of metabolism forthe added chemical arrangement is adjusted so as to produce a shorterduration of action for the modified drug as compared to the parent drug.11. The method of claim 10, in which the shorter duration allows themodified drug to be under precise moment-to-moment control by adjustmentof the infusion rate of the modified drug when administeredintravenously.
 12. The method of claim 11, in which the intravenousadministration is used to treat critical care patients.
 13. The methodof claim 11, in which the intravenous administration is used to treatneonates.
 14. The method of claim 11, in which the intravenousadministration is used to wean a patient off an unmodified parent drugwhose similar pharmacologic action is more safely removed in acontrolled, step-wise manner by progressively decreasing the rate of theintravenous drip of the modified drug.
 15. The method of claim 10, inwhich the shorter duration allows the actions of the modified drug toremain localized when the initial delivery or activation of the modifieddrug is targeted to a specified compartment by use of localizedinjection or implant materials, or by localized photodynamic activationof the modified drug.
 16. The method of claim 15, in which the implantis a type of surgical-related material or suture wherein the modifieddrug is an antibiotic or a compound that promotes wound healing.
 17. Themethod of claim 1, in which a programmed rate of metabolism of themodified drug is matched with a release rate from a sustained-releaseinjectable formulation or implant of the modified drug to provide forprolonged steady-state levels of the modified drug at pre-calibratedconcentrations.
 18. The method of claim 1, in which the modified drug isused as a topical treatment in order to eliminate or lessen unwantedeffects that the unmodified parent drug exhibits upon systemicabsorption after placement on the skin or within the eye or nasalpassageways.
 19. The method of claim 1, in which the parent drug plusadded chemical arrangement comprises a short-acting anti-cholinergicagent.
 20. The method of claim 19, in which the short-actinganti-cholinergic agent is an atropine derivative that is designed fortopical administration to the eye.
 21. The method of claim 19, in whichthe short-acting anti-cholinergic agent is a non-depolarizingneuromuscular junction blocking agent that is designed for use by theintravenous route during surgical-related procedures.
 22. The method ofclaim 1, in which the parent drug plus added chemical arrangementcomprises an ultra-short acting alpha₁-adrenergic receptor blocker or analpha₂-adrenergic receptor agonist.
 23. The method of claim 1, in whichthe parent drug plus added chemical arrangement comprises a short-actinginhibitor of the sodium channel.
 24. The method of claim 23, in whichthe short-acting inhibitors are administered as sustained-release orimplantable dosage forms.
 25. The method of claim 1, in which the parentdrug plus the added chemical arrangement comprises an ultra-short actingACE inhibitor.
 26. The method of claim 1, in which the parent drug plusthe added chemical arrangement comprises an ultra-short acting histaminereceptor blocker.
 27. The method of claim 1, in which the parent drugplus the added chemical arrangement comprises an ultra-short actingadenosine antagonist.
 28. The method of claim 1, in which the parentdrug plus the added chemical arrangement comprises an ultra-short actinganti-inflammatory agent.
 29. The method of claim 1, in which the parentdrug plus the added chemical arrangement comprises an ultra-short actingantiarrhythmic agent.
 30. The method of claim 1, in which the parentdrug plus the added chemical arrangement comprises an ultra-short actingcalcium channel blocker.
 31. The method of claim 1, in which the parentdrug plus the added chemical arrangement comprises an ultra-short actingantibiotic compound including sulfonamide, penicillin, cephalosporin ortetracycline.
 32. The method of claim 31, in which the ultra-shortacting antibiotic compounds are administered via impregnation insurgical suture material or wound-healing implantable polymericmaterials.
 33. The method of claim 1, in which the parent drug plus theadded chemical arrangement comprises a short-acting version ofmethotrexate.
 34. The method of claim 33, in which the short-actingversion of methotrexate is administered topically.
 35. The method ofclaim 34, in which the topical administration is used to treatepidermoid cancers or psoriasis.
 36. A method of treating a criticallyill patient comprising the step of using the modified drug of claim 1 byintravenous administration such that the drug's desirable effects arequickly equilibrated during infusion and are quickly dissipated when theinfusion is stopped.
 37. The use of the modified drug of claim 36 towean patients from a₂-adrenergic agonist treatment regimens byintravenous administration such that the drug's effects undergocontrolled withdrawal and do not prompt rebound hypertension.